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EFFECTS OF AGE-RELATED GLIAL ACTIVATION ON NEURITE
OUTGROWTH
by
Angela May Wong
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
May 2007
Copyright 2007 Angela May Wong

Declines in cognitive function are common during aging even in the absence of disease. Increased glial activation and inflammation during normal brain aging are implicated in neuron atrophy which may lead to cognitive impairments. Mechanisms underlying glial activation and their consequences on synaptic plasticity are explored in this thesis.; Macrosialin, a marker for activated for activated microglial cells, increases with age in various brain regions. These age-related increases could be attenuated with caloric restriction. In vitro studies showed that oxidized low density lipoproteins and inflammatory stimuli regulate macrosialin expression.; Apolipoproteins (Apo) E and J increase in several disease models and normal brain aging. However, basal Apo J secretion decreases with age in mixed glial cells originated from neonatal, young, and old animals. ApoE levels did not change significantly. While neonatal mixed glia were unaffected by the inflammatory cytokines, IL-1beta, IL-6, and TNF-alpha, adult mixed glia had different responses to IL-6 versus IL-1beta and TNF-alpha. IL-6 increased ApoE secretion while IL-1beta and TNF-alpha increased ApoJ secretion.; Neuroinflammation is implicated in neuron atrophy so an in vitro glial-neuron co-culture model was used to study the effects of glial cells activated by the inflammatory stimulus, lipopolysaccharide (LPS), on neurite sprouting. Activated glial cells secreted elevated levels of nitric oxide which persisted after LPS removal. Neurite sprouts decreased on LPS-treated glia. ApoE secretion decreased while ApoJ secretion increased in LPS-stimulated glia which may be an important mechanism underlying decreased neurite sprouting in the presence of inflammation.; Finally, effects of the ovarian steroid, progesterone (P4), on compensatory sprouting were studied in the in vivo entorhinal cortex lesioning (ECL) and in vitro "wounding-in-a-dish" models. Both P4 and 17beta-estradiol (E2) affect glial cells and inflammation. E2 has been shown to induce compensatory sprouting in vivo and in vitro, but interactions between P4 and E2 are not known. This study showed that P4 antagonizes E2-induced neurite sprouting in the presence of microglia. However, when microglial levels are low, P4 induces neurite outgrowth and synergizes with E2 in vitro. This may have important implications when interpreting the data on the effects of hormone replacement therapy on cognition.

EFFECTS OF AGE-RELATED GLIAL ACTIVATION ON NEURITE
OUTGROWTH
by
Angela May Wong
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
May 2007
Copyright 2007 Angela May Wong